Chemoimmunotherapy Shows 3-Year Survival Benefit for Advanced NSCLC

Adam J. Schoenfeld, MD

Medical Oncologist

Memorial Sloan-Kettering Cancer Center

New York, NY

Targeted Oncology^TM: What are the major trials comparing immunotherapy, chemoimmunotherapy, and chemotherapy alone for non–small cell lung cancer (NSCLC)?

SCHOENFELD: [There is an] ever-growing list of potential options you can treat patients with in the frontline lung cancer setting. And this is, of course, with patients who don’t have oncogene drivers that you would treat with targeted therapies that are excluded from these studies.

The first trial is CheckMate 227 [NCT02477826], which involves the drug regimen of nivolumab [Opdivo] plus ipilimumab [Yervoy] versus nivolumab alone versus platinum doublet chemotherapy. The second one is CheckMate 9LA [NCT03215706], which explored the regimen of 2 cycles of chemotherapy plus nivolumab and ipilimumab versus 4 cycles of platinum doublet chemotherapy. The final one is KEYNOTE-407 [NCT02775435], which is the study of pembrolizumab [Keytruda] plus carboplatin with paclitaxel, or pembrolizumab plus carboplatin plus nab-paclitaxel in patients with squamous histology disease, versus carboplatin plus paclitaxel or nab-paclitaxel.

Please describe the CheckMate 9LA trial of nivolumab/ipilimumab plus chemotherapy.

CheckMate 9LA was a randomized controlled trial comparing nivolumab at a dose of 360 mg every 3 weeks, plus ipilimumab at a dose of 1 mg/kg every 6 weeks plus [2 cycles of] chemotherapy versus [4 cycles of] chemotherapy. That is different than the melanoma regimen, where patients receive higher doses of ipilimumab.¹ The key eligibility criteria excluded patients with EGFR or ALK mutations. They needed to have a performance status of 0 or 1, and they were stratified by PD-L1 expression. The primary end point was overall survival (OS), and the secondary end points were progression-free survival (PFS), overall response rate (ORR), and efficacy by PD-L1 expression status.

What recent data was presented for this study?

The 3-year update was presented at the 2022 American Society of Clinical Oncology Annual Meeting. The investigators presented the [data] for OS in all patients randomized at the 3-year update. Patients with the nivolumab/ipilimumab plus chemotherapy regimen had a median OS of 15.8 months versus chemotherapy, which was 11.0 months.² The Kaplan-Meier curve shows the separation ongoing at 3 years, where OS is 27% among patients who received the combination versus 19% of patients who did not.

Looking at some of the secondary end points at the 3-year update, you see the median PFS for the nivolumab/ipilimumab/chemotherapy combination was 6.4 months versus 5.3 months for chemo, with a hazard ratio of 0.7 [95% CI, 0.59-0.83]. The ORR for nivolumab/ipilimumab plus chemotherapy was also higher than chemotherapy alone, 38% versus chemotherapy’s [ORR] of 25%. The ongoing responses at 3 years were 23% for nivolumab/ipilimumab plus chemotherapy versus 14% for chemotherapy [alone].

What stood out about the PD-L1 negative and positive groups?

Stratified by PD-L1 expression, there was superior survival in PD-L1–positive patients as well as, strikingly, in PD-L1–negative patients, where at 3 years the OS for PD-L1–negative patients, 25% for the nivolumab/ipilimumab plus chemotherapy versus 15% for the chemotherapy. The tail of the curve [flattened] on the PD-L1 negative side, and in the PD-L1 positive, similarly the separation between OS in the 2 groups.

Then, with PD-L1 expression greater than 50%, we similarly see a difference in survival between the 2 groups, showing that there really is a separation in survival in all PD-L1 groups, including PD-L1 negative patients.

It is interesting that the PD-L1–negative group had a better survival than the PD-L1–positive group. And, somewhat counterintuitively in general, that the PD-L1–negative group would have a more profound response difference between the patients that received the nivolumab/ipilimumab versus those that didn’t, because the PD-L1 biomarker is the predictive marker for checkpoint blockade with PD-L1 blockade.

What was the toxicity reported with this combination?

[The following are] some of the treatment-related adverse events [AEs] with nivolumab/ipilimumab plus chemotherapy. We’re focusing on those AEs with potential immunologic etiology that require frequent monitoring and intervention. The most common AEs related to this that we see are skin toxicity, occurring in approximately 40% of patients.^3,4 The grade 3 to 4 [skin toxicities] occur in roughly 4% of patients. And then, endocrine toxicity was the second most common AE, occurring in 26% of patients, followed by gastrointestinal, hepatic, renal pulmonary, and hypersensitivity reactions.

[When comparing] the toxicities typically associated with chemotherapy among the nivolumab/ipilimumab plus chemotherapy group versus the chemotherapy, it shows that there’s somewhat comparable toxicity in the 2 groups. Given that you’re only giving 2 doses of chemotherapy in the nivolumab/ipilimumab plus chemotherapy group, you do see somewhat less development of anemia, and neutropenia, and the related toxicities. But overall, there are somewhat comparable toxicities to the extent that they arise in both groups.

How did treatment discontinuation affect survival outcomes for patients who received the combination chemoimmunotherapy?

The data show the efficacy in patients who discontinued nivolumab/ipilimumab plus chemotherapy due to treatment-related AEs. For patients who discontinued all components due to treatment-related AEs, the median OS was 27.5 months, and the 2-year OS rate was 54%.⁵ The median duration of response after discontinuation was 14.5 months, with 56% of patients having ongoing responses for greater than 1 year after discontinuation.

_References:

_{1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34. doi:10.1056/NEJMoa1504030}

_{2. Paz-Ares LG, Ciuleanu TE, Cobo-Dols M, et al. First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients (pts) with metastatic non–small cell lung cancer (NSCLC): 3-year update from CheckMate 9LA. J Clin Oncol. 2022;40(17_suppl):LBA9026-LBA9026. doi:10.1200/JCO.2022.40.17_suppl.LBA9026}

_{3. Reck M, Cileanu TE, Cobo-Dols M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol. 2020;38(15_suppl):9501:9501. doi: 10.1200/JCO.2020.38.15_suppl.9501}

_{4. Paz-Ares L, Ciuleanu TE, Cobo-Dols M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):198-211. doi:10.1016/S1470-2045(20)30641-0}

_{5. Reck M, Ciuleanu TE, Cobo-Dols M, et al. First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from CheckMate 9LA. J Clin Oncol. 2021;39(15_suppl):9000-9000. doi:10.1200/JCO.2021.39.15_suppl.9000}